Rotary blending apparatus and system

ABSTRACT

A rotary blending apparatus and system comprising a hub ( 10 ) and a plurality of substantially angularly spaced impeller blades ( 20 ). The unique, variable configuration of the impeller blades produces optimum flow patterns and, hence, highly efficient mixing of solids and liquids. The blending apparatus is also scalable to multiple sizes without compromising mixing performance.

FIELD OF THE PRESENT INVENTION

The present invention relates generally to blending systems. Moreparticularly, the invention relates to a blending apparatus and systemfor mixing compositions, particularly, dry powder pharmaceuticalcompositions.

BACKGROUND OF THE INVENTION

It is well known that pharmaceutical compositions in the form of a drypowder may advantageously be administered by inhalation to or throughthe lung of a patient. In inhalation therapy, a pharmaceutical deliverydevice, such as a dry powder inhaler (“DPT”), is typically employed todeliver a prescribed dose of a pharmaceutical composition and, hence,medicament to the pulmonary system of a patient. As is well known in theart, in a typical DPI, a dose of the pharmaceutical composition ispositioned in an aerosolization chamber, where it is aerosolized and,hence, dispersed into respirable particles by airflow supplied by apressurized source of gas or by the patient's inspiration effort. It isalso well known in the art that in order to settle in the appropriateregions of the lung associated with local and/or systemic drug delivery,the dispersed particles must be of suitable size.

The pulmonary system includes the upper airways, including theoropharynx and larynx, followed by the lower airways, which include thetrachea followed by bifurcations into bronchi and bronchioli. The upperand lower airways are called the conducting airways. The terminalbronchioli then divide into respiratory bronchioli, which then lead tothe alveolar region, or the deep lung. See, Gonda, I, “Aerosols forDelivery of Therapeutic and Diagnostic Agents to the Respiratory Tract”,Critical Reviews in Therapeutic Drug Carrier Systems, vol. 6, pp.273-313 (1990).

The smooth muscle regions of the conducting airways, and particularlythe lower airways, possess receptors (i.e., protein based,macromolecular complexes existing within cell membranes which, uponinteraction with specific agents, change conformation and lead to thetriggering of a cellular response, such as smooth muscle cellcontraction or relaxation) that are the primary target site of localmedicament particle delivery. The alveolar region of the deep lung,although it too may possess receptors effecting local response, is thetarget site for pulmonary systemic delivery, as the alveoli provideaccess to vascular system through a closely associated vascularcapillary network.

It is well known that medicament particles deposit in specific areas ofthe pulmonary system based upon the aerodynamic size of the particlesand the flow rate of the fluid within which they are entrained.Typically, with average inhalation flow rates of between 10 and 60liters per minute, particles having an aerodynamic diameter in the rangeof 0.5 to 3 μm are suitable for systemic delivery, as these particlesdeposit selectively in the deep lung. Particles having an aerodynamicdiameter in the range of approximately 0.5 to 10 μm, preferably, 1 to 6μm, and more preferably, 3 to 6 μm are suitable for local lung delivery,as they will deposit in the conductive airways.

Particles having an aerodynamic diameter greater than 10 μm generallydeposit in the mouth, throat or upper airways, offering littletherapeutic benefit. Particles having an aerodynamic diameter less than0.5 μm do not settle out of the airflow to deposit in the lungs, and aresubsequently respired when the patient exhales.

The effectiveness of dry powder pharmaceutical composition delivery thusdepends upon the ability to precisely and reproducibly meter smallquantities of medicament into doses. The metering is typically achievedby diluting the medicament in a pharmaceutical composition. Thepharmaceutical composition can then be metered with a greater margin oferror than a highly potent medicament alone.

The pharmaceutical compositions are desirably highly aerosolizable toclear the composition from the inhaler device and disperse thecomposition into particles of respirable size. Measurements ofaerosolizibility and dispersiblity may be made by measuring the emitteddose and fine particle fraction of the composition, respectively, usingmethodologies known to the art. A common device used in measuring fineparticle fraction is an Anderson Cascade Impactor.

It is further desired that the pharmaceutical composition besufficiently flowable to permit the composition to be poured orotherwise transferred into individual doses. Measures of flowability aretypically quantified by the compressibility of the powder composition,as well as its “angle of repose.” The measurement of these features istypically made using standardized methodologies known in the art.

Efforts in the area of meterability have long included the use ofexcipients, such as milled or micronized lactose, to dilute themedicament in the pharmaceutical composition, allowing microgramquantities of very potent medicaments to be precisely metered intomilligram sized doses with an acceptable degree of control. Blending ofthe excipient(s) and medicament must, however, provide a dry powderpharmaceutical composition that exhibits substantial homogeneity withrespect to the medicament and uniformity of particle size distribution.Indeed, the noted criteria are essential to ensure that the correcttherapeutic dose of the medicament is delivered to the patient.

Various conventional blending apparatus and systems have been employedin an effort to produce homogenous, uniform dry powder pharmaceuticalcompositions. Such systems include tumble mixers and high shear impellerdesign systems. The conventional systems are, however, often fraughtwith numerous disadvantages and drawbacks. Among the disadvantages arethe unacceptably high power input required per unit volume of blend,system complexity and high cost. Further, the mixer blade or impellerdesign that is employed is often limited in its ability to provide anoptimum flow pattern over a range of power input and be scaled up (ordown) without compromising blending performance.

Thus, there exists a need to provide a blending apparatus and systemthat consistently provides an optimum flow pattern over a broad range ofpower input and, hence, optimum blending performance. There also existsa need to provide a blending apparatus and system that can be readilyscaled up or down without compromising blending performance.

It is therefore an object of the present invention to provide a blendingapparatus and system that overcomes the aforementioned disadvantages anddrawbacks associated with conventional blending apparatus and systems.

It is another object of the present invention to provide a blendingapparatus and system that is capable of creating optimum motion or flowof the blend (e.g., powder) for a given amount of energy expended.

It is another object of the present invention to provide a blendingapparatus and system that is capable of creating optimum motion or flowof the blend over a broad range of power input.

It is another object of the invention to provide a blending apparatusand system that is capable of achieving the required process performancewith less power and in a shorter period of time as compared toconventional blending systems.

It is another object of the invention to provide a blending apparatusand system that produces substantially homogenous pharmaceuticalcompositions that are suitable for inhalation therapy.

It is yet another object of the invention to provide a blendingapparatus and system that produces pharmaceutical compositions having ahigh degree of aerosolibility and dispersability.

SUMMARY OF THE INVENTION

In accordance with the above objects and those that will be mentionedand will become apparent below, the rotary blending apparatus and systemin accordance with this invention comprises a hub having an outerdiameter and a plurality of substantially angularly spaced impellerblades, each of the impeller blades having a first and second baffle,the first baffle having a first end rigidly connected to the hub andforming a first impeller angle with respect to the vertical axis of thehub in the range of approximately 110°-130°, the second end of saidfirst baffle having a substantially lineai edge forming a secondimpeller angle with respect to the longitudinal axis of the hub in therange of 40°-50°, the second baffle being rigidly connected to thesecond end of the first baffle whereby the first and second baffles forma third impeller angle in the range of approximately 85°-95°.

In one embodiment of the invention, the geometric and dimensionalrelationship of the hub and impellers define a first blending apparatussize that provides a first flow pattern of the blend (or composition)during mixing.

In a preferred embodiment, the blending apparatus is scalable to atleast a second blending apparatus size that provides a second flowpattern that is substantially similar to the first flow pattern.

The advantages of this invention include the provision of a blendingapparatus (i.e., impeller) and system that is capable of producingoptimum flow patterns and, hence, substantially homogenouspharmaceutical compositions having a substantially uniform particle sizedistribution and a high degree of aerosolibility and dispersability. Afurther advantage is the capability of the blending apparatus to bereadily scaled up or down without compromising blending performance.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages will become apparent from the followingand more particular description of the preferred embodiments of theinvention, as illustrated in the accompanying drawings, and in whichlike referenced characters generally refer to the same parts or elementsthroughout the views, and in which:

FIG. 1 a perspective view of one embodiment of the blending apparatusaccording to the invention;

FIG. 2 is a top plan view of the blending apparatus shown in FIG. 1,according to the invention;

FIG. 3 is a partial side elevational view of the blending apparatusshown in FIG. 1, according to the invention;

FIG. 4 is a partial sectional front elevational view of the blendingapparatus shown in FIG. 1, according to the invention;

FIG. 5 is a right side elevational view of the blending apparatus shownin FIG. 1, according to the invention;

FIG. 6 is a left side elevational view of the blending apparatus shownin FIG. 1, according to the invention;

FIG. 7 is a schematic illustration of a preferred blend flow patternresulting from the blending apparatus of the invention;

FIG. 8 is a schematic illustration of the mechanical impact and shearforces imparted on a blend by the blending apparatus of the invention;

FIG. 9 is a graphical illustration of the relationship of the impact andshear forces as a function of the second impeller angle, according tothe invention; and

FIG. 10 is an elevational view of one embodiment of the blending system,according to the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particularlyexemplified method or process parameters as such may, of course, vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments of the invention only, andis not intended to limit the scope of the invention in any manner.

All publications, patents and patent applications cited herein, whethersupra or infra, are hereby incorporated by reference in their entirety.

It must also be noted that, as used in this specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the content clearly dictates otherwise.

Further, unless defined otherwise, all technical and scientific termsused herein have the same meaning as commonly understood by one ofordinary skill in the art to which the invention pertains. Although anumber of methods and materials similar or equivalent to those describedherein can be used in the practice of the present invention, thepreferred materials and methods are described herein.

In describing the present invention, the following terms will beemployed, and are intended to be defined as indicated below.

Definitions

By the term “medicament”, as used herein, is meant to mean and includeany substance (i.e., compound or composition of matter) which, whenadministered to an organism (human or animal) induces a desiredpharmacologic and/or physiologic effect by local and/or systemic action.The term therefore encompasses substances traditionally regarded asactives, drugs and bioactive agents, as well as biopharmaceuticals(e.g., peptides, hormones, nucleic acids, gene constructs, etc.),including, but not limited to, analgesics, e.g., codeine,dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations,e.g., diltiazem; antiallergics, e.g., cromoglycate (e.g., as the sodiumsalt), ketotifen or nedocromil (e.g., as the sodium salt);antiinfectives, e.g., cephalosporins, penicillins, streptomycin,sulphonamides, tetracyclines and pentamidine; antihistamines, e.g.,methapyrilene; anti-inflammatories, e.g., beclomethasone (e.g., as thedipropionate ester), fluticasone (e.g., as the propionate ester),flunisolide, budesonide, rofleponide, mometasone (e.g., as the furoateester), ciclesonide, triamcinolone (e.g., as the acetonide) or6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester; antitussives, e.g.,noscapine; bronchodilators, e.g., albuterol (e.g., as free base orsulfate), salmeterol (e.g., as xinafoate), ephedrine, adrenaline,fenoterol (e.g., as hydrobromide), formoterol (e.g. as fi umarate),isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol (e.g., as acetate), reproterol (e.g., as hydrochloride),rimiterol, terbutaline (e.g., as sulfate), isoetharine, tulobuterol or4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone;adenosine 2a agonists, e.g.,(2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol(e.g., as maleate); α₄ integrin inhibitors e.g.(2S)-3-[4-({[4-(aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino]propanoicacid (e.g., as free acid or potassium salt), diuretics, e.g .,amiloride; anticholinergics, e.g., ipratropium (e.g. as bromide),tiotropium, atropine or oxitropium; hormones, e.g., cortisone,hydrocortisone or prednisolone; xanthines, e.g., aminophylline, cholinetheophyllinate, lysine theophyllinate or theophylline; therapeuticproteins and peptides, e.g., insulin or glucagon. The noted medicamentsmay also be employed in the form of salts, (e.g., as alkali metal oramine salts or as acid addition salts) or as esters (e.g., lower alkylesters) or as solvates (e.g., hydrates) to optimize the activity and/orstability of the medicament.

The term “medicament ” further includes formulations containingcombinations of active ingredients, including, but not limited to,salbutamol (e.g., as the free base or the sulfate salt) or salmeterol(e.g., as the xinafoate salt) or formoterol (e.g., as the fumarate salt)in combination with an anti-inflammatory steroid such as abeclomethasone ester (e.g., the dipropionate), a fluticasone ester(e.g., the propionate), a furoate ester or budesonide.

By the term “pharmaceutical composition”, as used herein, it is meant tomean a combination of at least one medicament and one or more addedcomponents or elements, such as an “excipient” or “carrier.” As will beappreciated by one having ordinary skill in the art, the terms“excipient” and “carrier” generally refer to substantially inertmaterials that are nontoxic and do not interact with other components ofthe composition in a deleterious manner. Examples of normally employed“excipients,” include pharmaceutical grades of carbohydrates includingmonosaccharides, disaccharides, cyclodextrins and polysaccharides (e.g.,dextrose, sucrose, lactose, raffinose, mannitol, sorbitol, inositol,dextrins and maltodextrins); starch; cellulose; salts (e.g., sodium orcalcium phosphates, calcium sulfate, magnesium sulfate); citric acid;tartaric acid; glycine; leucine; high molecular weight polyethyleneglyols (PEG); pluronics; surfactants; lubricants; stearates and theirsalts or esters (e.g., magnesium stearate, calcium stearate); aminoacids; fatty acids; and combinations thereof. Examples of suitable“carriers” include water, silicone, gelatin, waxes, and like materials.

By the terms “blend” and “composition”, as used herein, it is meant tomean one or more substances or elements in the form of a powder orliquid or combination thereof. The term “composition” thus includes drypowder pharmaceutical compositions and the aforementioned medicaments.

By the term “mixing”, as used herein, it is meant to mean and includeblending, dispersion and emulsifying of a “blend” or “composition”.

By the term “pharmaceutical delivery device”, as used herein, it ismeant to mean a device that is adapted to administer a controlled amountof a composition to a patient, including, but not limited to, theDiskus® device disclosed in U.S. Pat Nos. Des. 342,994; 5,590,654,5,860,419; 5,837,630 and 6,032,666; the Diskhaler™ device disclosed inU.S. Pat. Nos. Des 299,066; 4,627,432 and 4,811,731; the Rotohaler™device disclosed in U.S. Pat. No. 4,778,054; the Cyclohaler™ device byNorvartis; the Turbohaler™ device by Astra Zeneca; the Twisthaler™device by Scheling Plough; the Handihaler™ device by BoehringerEngelheim; the Airmax™ device by Baker-Norton; and the Dura and InhaledTherapeutic active delivery systems. Each of the noted “pharmaceuticaldelivery devices” are incorporated by reference herein.

As will be appreciated by one having ordinary skill in the art, thepresent invention substantially reduces or eliminates the disadvantagesand drawbacks associated with conventional blending apparatus andsystems. As discussed in detail below, the blending apparatus and systemof the invention provides an optimum, highly turbulent flow regimeduring the mixing (or blending) process, resulting in substantiallyhomogeneous dry powder pharmaceutical compositions that are particularlysuitable for inhalation therapy. The blending apparatus and system alsoallows broad ranges of power input and impeller tip speeds to beemployed without adversely affecting the mixing performance and, hence,homogeneity of the pharmaceutical compositions. The ability to employ abroad range of power input and the control thereof further facilitates ahigh degree of control of the fine particle mass (FPM) performance ofthe pharmaceutical compositions.

Referring now to FIGS. 1 and 2, there is shown the blending apparatus 5of the invention. As illustrated in FIG. 1, the blending apparatus 5includes a hub 10 and a plurality of substantially equally spacedimpeller blades 20 attached thereto.

According to the invention, the hub 10 is adapted to receive andoperatively engage a rotatable blending system shaft 48 (see FIG. 8). Inone embodiment of the invention, illustrated in FIGS. 2 and 4, the hub10 comprises a substantially circular member having an interior portion12 and shaft seat 14. The hub 10 preferably has an outer diameter d inthe range of 139.0 to 141.0 mm, more preferably, 139.8 to 140.2 mm (seeFIG. 5).

To facilitate engagement of the hub 10 to the rotatable system shaft 48,the hub 10 includes a pair of equally spaced holes 16 that arepreferably disposed on the shaft seat 14. As illustrated in FIG. 2, alsodisposed centrally on the shaft seat 14 is a shaft engagement slot 18.

Referring back to FIGS. 1 and 2, each impeller blade 20 of the inventionincludes first and second baffles 22, 26. The first baffle 22 ispreferably a substantially flat, elongated member having first andsecond planar surfaces 23 a, 23 b and a root portion 24 proximate to thehub 10.

According to the invention, the first baffle 22 preferably has a lengthl₁ in the range of 245.0 to 247.0 mm and a width w₁ in the range of 70.0to 75.0 mm (see FIGS. 3 and 5). More preferably, the length l₁ is in therange of 246.0 to 246.75 mm and the width w₁ is in the range of 72.0 to74.0 mm.

The second baffle 26 preferably has a length l₂ in the range of 139.0 to141.0 mm and a width w₂ in the range of 96.0 to 98.0 mm (see FIG. 6).More preferably, the length l₂ is in the range of 139.8 to 140.2 mm andthe width w₂ is in the range of 96.8 to 97.2 mm.

In a preferred embodiment of the invention, the first baffle 22 forms afirst impeller angle α with respect to the vertical axis of the hub 10(designated A) in the range of approximately 110°-130° thatsubstantially uniformly extends from the root portion 24 to the distalend 25 of the first baffle 22 (see FIG. 3). More preferably, the firstimpeller angle α is approximately 120°.

Referring to FIG. 2, the distal end 25 of the first baffle 22 preferablyforms a second impeller angle β with respect to the longitudinal axis ofthe first baffle 22 (designated B) in the range of approximately40°-50°. More preferably, the second impeller angle β is approximately45°.

Referring now to FIGS. 1 and 4, the second baffle 26 is similarlypreferably a substantially flat, elongated member having first andsecond planar surfaces 27 a, 27 b, an engagement portion (or end) 28 anda tip portion.30. As illustrated in FIG. 4, the engagement end 28 isconnected to the distal end 25 of the first baffle 26. Preferably, thefirst baffle 22 and second baffle 26 form a third impeller angle Φ inthe range of approximately 85°-95°. More preferably, the third impellerangle is approximately 90°.

According to the invention, α, β, Φ, d, l₁, l₂, w₁ and w₂ define a coregeometric and dimensional relationship. In one embodiment of theinvention, α, β, Φ, d, l₁, l₂, w₁ and w₂ further define a first blendingapparatus size having a tip radius r₁. According to the invention, thefirst blending apparatus size provides a flow pattern FP substantiallyas illustrated in FIG. 7 and discussed in detail below.

Referring back to FIG. 4, the tip portion 30 of the second baffle 26preferably includes a substantially flat tip edge 32. According to oneembodiment of the invention, the tip edge 32 is preferably substantiallyparallel to the horizontal plane (designated generally P′) formed by thefirst baffle(s) 22.

Preferably disposed on the radial portion of the tip edge 32 is a tiprelief 34. According to the invention, the tip relief 34 forms a reliefangle Ø with respect to the leading edge 31 of the second baffle 26 thatis preferably in the range of approximately 25° to 35°.

Advantageously, in one embodiment, the outside comer of the tip edge maybe removed so as to allow the impeller to be fitted and removed withlittle, if any, in-bowl assembly or sunken bolts.

In a preferred embodiment, the blending apparatus 5 is constructed outof a material suitable for pharmaceutical processes, such as stainlesssteel. The hub 10 and first and second baffles 22, 26 are alsopreferably interconnected by welding to form an integrated one-pieceunit.

As indicated above, a key advantage of the blending apparatus 5 (and,hence, system 40) of the invention is that it is readily scalable, i.e.,scaled up or down, to at least a second blending apparatus size having atip radius r₂ that provides a flow pattern FP′ that is substantiallyequal to FP; provided, (i) the container clearance (designated C_(c) inFIG. 8 and discussed in detail below) is maintained in the range of 2 to3 mm, (ii) the impeller angles α, β and Φ are maintained within theabove recited preferred ranges, and (iii) the core geometric anddimensional relationship of d, l₁, l₂, w₁, and w₂ is maintained, i.e.,d ₁ =SF×d  Eq. 1l ₃ =SF×l ₁  Eq. 2l ₄ =SF×l ₂  Eq. 3w ₃ =SF×w ₁  Eq. 4w ₄ =SF×w ₂  Eq. 5where

SF=scale factor (e.g., 1.3);

d₁=hub diameter of scaled blending apparatus;

l₃=first baffle length of scaled blending apparatus;

l₄=second baffle length of scaled blending apparatus;

w₃=first baffle width of scaled blending apparatus; and

w₄=second baffle width of scaled blending apparatus.

Referring now to FIG. 7, there is shown a schematic illustration of thevariable and, hence, highly turbulent flow pattern achieved by virtue ofthe blending apparatus 5 of the invention (designated generally FP).According to the invention, during rotation of the blending apparatus 5in a direction denoted by Arrow R, the blend (e.g., dry powderpharmaceutical composition) passing over the impeller blades 20 flows inmultiple directions, including upwardly by virtue of the second planarsurface 23 b of the first baffle 22 and first impeller angle α andsubstantially rotationally proximate each impeller blade 20, denoted byArrows F_(L), F_(L)′, F_(L)″, by virtue of the second planar surface 27b of the second baffle 26 and second impeller angle β.

More particularly, the impeller blades 20 impart from the periphery ofthe mixing container 42 to the blend an inwardly directed, high velocitythrust having a dominating axial component that creates an intensehydraulic s hear in the blend. At the same time, the impeller blades 20also impart to each of the blend streams a mechanical shear force(discussed below) that further contributes to the blending anddispersion of the blend.

Applicants have further found that the reverse flow of the blend,denoted by Arrows F_(L)″, substantially reduces, and in most instanceseliminates, the effects of an increasing pressure drop across theimpeller blades 20, which is often encountered with conventionalimpellers.

Referring now to FIG. 8, there is shown a schematic illustration of themechanical impact and shear forces, denoted F_(I), F_(S), respectively,generally imparted on the blend by each impeller blade 20. Asillustrated in FIG. 8, the mechanical impact force, F_(I), is generallyimparted in a direction substantially perpendicular to the impellerblade 20. The mechanical shear force, F_(S), is generally imparted tothe blend in a direction approximately parallel to the longitudinal axisof the impeller blade 20 (i.e., axially).

According to the invention, the ratio of F_(I)/F_(S), which is a keyfactor in achieving desired blending performance, can be varied as afunction of the second impeller angle β. As illustrated in FIG. 9, theratio F_(I)/F_(S) can be determined from the following relationship:1/tan β=F _(I) /F _(S)  Eq. 6

As indicated above, in one embodiment of the invention, a secondimpeller angle β of approximately 45° is employed. The noted secondimpeller angle β thus yields a substantially equal ratio of F_(I)/F_(S).

Applicants have found the noted relationship provides an optimum, highlyturbulent flow pattern over broad ranges of power input (e.g., 600-900W) and blend volumes (e.g., 12 kg to 25 kg). The noted relationship alsoallows significantly higher impeller tip speeds to be employed (e.g.,140 to 300 rpm) without compromising blending performance.

As will be appreciated by one having ordinary skill in the art, the flowpattern produced by the blending apparatus 5 described above can bevaried and/or tailored to achieve a specific mixing parameter (orregime) by varying the core geometric and dimensional relationship. Theblending apparatus 5 can similarly be tailored to accommodate effectivemixing of various forms of blends (e.g., liquid, slurry, etc.).

Referring now to FIG. 10, there is shown one embodiment of the blendingsystem 40 of the invention. The blending system 40 includes the blendingapparatus 5 described above, a mixing container 42, power transmissionmeans (e.g., motor) 44, a drive assembly 46, a rotatable shaft 48 andcontrol means 50.

The mixing container 42 of the invention is preferably constructed outof stainless steel or like material and has a substantially circularshape. The container 42 also includes conventional means (e.g., ports)for receiving and discharging the blend 100 (not shown).

According to the invention, the power transmission means 44 isoperatively connected to the drive assembly 46, which, in turn, isconnected to and rotates the rotatable shaft 48. As indicated above, therotatable shaft 48 is adapted to engage the hub 10 of the blendingapparatus 5 and, hence, impart rotational energy thereto.

As will be appreciated by one having ordinary skill in the art, variouspower transmission means may be employed within the scope of theinvention to drive the drive assembly 46. In a preferred embodiment, thepower transmission means comprises a 7.5 kw motor.

Similarly, various control means 50 can be employed to control the powertransmission means 44 and drive assembly 46 of the invention.Preferably, the control means 50 comprises a computer that is programmedand adapted to monitor and regulate the power input and tip speed of theblending apparatus 5.

As indicated above, the blending apparatus and system of the inventionis capable of producing optimum flow patterns and, hence, substantiallyhomogenous dry powder pharmaceutical compositions having a substantiallyuniform particle size distribution and a high degree of aerosolibilityand dispersability. The pharmaceutical compositions are thusparticularly suitable for inhalation therapy. Accordingly, a furtheraspect of the present invention comprises pharmaceutical compositions,including particulate medicament particles (i.e., neat drugs), blendedin accordance with the present invention.

It will be appreciated by those skilled in the art that thepharmaceutical compositions blended in accordance with the inventioncan, if desired, contain a combination of two or more medicaments orcomponents, including combinations of bronchodilatory agents (e.g.,ephedrine and theophylline, fenoterol and ipratropium, and isoetharineand phenylephrine formulations).

Other pharmaceutical compositions may contain bronchodilators such assalbutamol (e.g. as the free base or as the sulphate salt), salmeterol(e.g. as the xinafoate salt), formoterol or isoprenaline in combinationwith an anti-inflammatory steroid such as a beclomethasone ester (e.g.the dipropionate) or a fluticasone ester (e.g. the propionate) or abronchodilator in combination with an antiallergic such as cromoglycate(e.g. the sodium salt). A particularly preferred combination is acombination of fluticasone propionate and salmeterol, or a salt thereof(particularly the xinafoate salt). A further combination is budesonideand formoterol (e.g., as the fumarate salt).

It is to be understood that the present invention covers each of thenoted medicaments and compounds, all physiologically acceptablederivatives thereof, and all combinations of particular and preferredgroups described hereinabove. The term “physiologically acceptablederivative”, as used herein, refers to any physiologically acceptablederivative of a compound of the present invention, for example, anester, which upon administration to a mammal, such as a human, iscapable of providing (directly or indirectly) such a compound or anactive metabolite thereof. Such derivatives are clear to those skilledin the art, without undue experimentation, and with reference to theteaching of Burger's Medicinal Chemistry And Drug Discovery, 5thEdition, Vol 1: Principles And Practice, which is incorporated herein byreference.

The pharmaceutical compositions blended in accordance with the inventioncan conveniently be filled into a bulk storage container, such as amulti-dose reservoir, or into unit dose containers such as capsules,cartridges or blister packs, which may be used with an appropriatepharmaceutical delivery device, for example, as described in GB2041763,WO91/13646, GB1561835, GB2064336, GB2129691 or GB2246299, which areincorporated by reference herein. The noted devices and aforementionedpharmaceutical delivery devices containing a pharmaceutical compositionblended in accordance with the invention are deemed novel and, hence,form a further aspect of the invention.

The pharmaceutical compositions formed in accordance with the inventionare particularly suitable for use with multi-dose reservoir-type devicesin which the composition is metered, e.g. by volume from a bulk powdercontainer into dose-metering cavities. The lower limit of powderdelivery, which may be accurately metered from a multi-dosereservoir-type device, is typically in the range of 100 to 200micrograms. The noted pharmaceutical compositions are thereforeparticularly advantageous for highly potent and, hence, low dosemedicaments that require a high ratio of excipient for use in amulti-dose reservoir-type device.

SUMMARY

From the foregoing description, one of ordinary skill in the art caneasily ascertain that the present invention provides a blendingapparatus and system that is capable of producing optimum flowpattern(s) over a range of power input and, hence, substantiallyhomogenous pharmaceutical compositions having a substantially uniformparticle size distribution and a high degree of aerosolibility anddispersability. A further advantage is the capability of the blendingapparatus to be readily scaled up or down without compromising blendingperformance.

Without departing from the spirit and scope of this invention, one ofordinary skill can make various changes and modifications to theinvention to adapt it to various usages and conditions. As such, thesechanges and modifications are properly, equitably, and intended to be,within the full range of equivalence of the following claims.

1. A rotary blending apparatus for mixing a composition, comprising: ahub; and a plurality of substantially angularly spaced impeller blades,each of said impeller blades having a first and second baffle, saidfirst baffle having first and second ends, said first end being rigidlyconnected to said hub, said first baffle forming a first impeller anglewith respect to the vertical axis of said hub in the range ofapproximately 110°-130°, said second end of said first baffle having asubstantially linear edge forming a second impeller angle with respectto the longitudinal axis of said hub in the range of 40°-50°, saidsecond baffle having first and second ends, said first end of saidsecond baffle being rigidly connected to said second end of said firstbaffle, said first and second baffles forming a third impeller angle inthe range of approximately 85°-95°.
 2. The apparatus of claim 1, whereinsaid composition comprises a dry powder.
 3. The apparatus of claim 2,wherein said dry powder comprises a pharmaceutical composition.
 4. Theapparatus of claim 1, wherein said hub has an outer diameter in therange of 139.0 to 141.0 mm.
 5. The apparatus of claim 1, wherein saidfirst baffle has a first length in the range of 245.0 to 247.0 mm and afirst width in the range of 70.0 to 75.0 mm.
 6. The apparatus of claim1, wherein said second baffle has a second length in the range of 139.0to 141.0 mm and a second width in the range of 96.0 to 98.0 mm.
 7. Theapparatus of claim 1, wherein each of said impellers impart impact andshear forces to said composition during rotation of said apparatus. 8.The apparatus of claim 7, wherein the ratio of said impact and shearforces is substantially equal to 1/tan (second impeller angle).
 9. Theapparatus of claim 1, wherein said first and second baffles comprisesubstantially flat, elongated members.
 10. The apparatus of claim 9,wherein said first impeller angle extends substantially uniformly fromsaid first end to said second end of said first baffle.
 11. Theapparatus of claim 1, wherein said hub outer diameter, said first andsecond lengths, said first and second widths, and said first, second andthird impeller angles define a first blending apparatus size have afirst tip radius, said first blending apparatus size providing a firstflow pattern of said composition during rotation of said apparatus. 12.The apparatus of claim 11, wherein said first flow pattern includes areverse flow component.
 13. The apparatus of claim 11, wherein saidapparatus is scalable to at least a second blending apparatus sizehaving a second tip radius, said second blending apparatus sizeproviding a second flow pattern that is substantially similar to saidfirst flow pattern.
 14. A rotary blending apparatus for mixing apharmaceutical composition, comprising: a hub having an outer diameterin the range of 139.0 to 141.0 mm; and a plurality of substantiallyangularly spaced impeller blades, each of said impeller blades having afirst and second baffle, said first baffle having first and second ends,a first length in the range of 245.0 to 247.0 mm and a first width inthe range of 70.0 to 75.0 mm, said first end of said first baffle beingrigidly connected to said hub, said first baffle forming a firstimpeller angle with respect to the vertical axis of said hub in therange of approximately 110°-130°, said second end of said first bafflehaving a substantially linear edge forming a second impeller angle withrespect to the longitudinal axis of said hub in the range of 40°-50°,said second baffle having first and second ends, a second length in therange of 139.0 to 141.0 mm and a second width in the range of 96.0 to98.0 mm, said first end of said second baffle being rigidly connected tosaid second end of said first baffle, said first and second bafflesforming a third impeller angle in the range of approximately 85°-95°,said hub outer diameter, said first and second lengths, said first andsecond widths, and said first, second and third impeller angles defininga first blending apparatus size have a first tip radius, said firstblending apparatus size providing a first flow pattern of saidcomposition during rotation of said apparatus, said apparatus beingscalable to at least a second blending apparatus size having a secondtip radius, said second blending apparatus size providing a second flowpattern that is substantially similar to said first flow pattern. 15.The apparatus of claim 14, wherein said pharmaceutical compositioncomprises a dry powder.
 16. The apparatus of claim 14, wherein each ofsaid impellers impart impact and shear forces to said composition duringrotation of said apparatus.
 17. The apparatus of claim 16, wherein theratio of said impact and shear forces is substantially equal to 1/tan(second impeller angle).
 18. The apparatus of claim 14, wherein saidfirst and second baffles comprise substantially flat, elongated members.19. The apparatus of claim 18, wherein said first impeller angle extendssubstantially uniformly from said first end to said second end of saidfirst baffle.
 20. The apparatus of claim 14, wherein said first flowpattern includes a reverse flow component.
 21. A rotary blending systemfor mixing a composition, comprising: a mixing container having a mixingchamber; a rotatable drive shaft; and a rotary blending apparatusdisposed in said mixing chamber, said rotary blending apparatus beingconnected to said drive shaft, said rotary blending apparatus includinga hub and a plurality of substantially angularly spaced impeller blades,each of said impeller blades having a first and second baffle, saidfirst baffle having first and second ends, said first end being rigidlyconnected to said hub, said first baffle forming a first impeller anglewith respect to the vertical axis of said hub in the range ofapproximately 110°-130°, said second end of said first baffle having asubstantially linear edge forming a second impeller angle with respectto the longitudinal axis of said hub in the range of 40°-50°, saidsecond baffle having first and second ends, said first end of saidsecond baffle being rigidly connected to said second end of said firstbaffle, said first and second baffles forming a third impeller angle inthe range of approximately 85°-95°.
 22. The system of claim 20, whereinsaid hub has an outer diameter in the range of 139.0 to 141.0 mm. 23.The system of claim 20, wherein said first baffle has a first length inthe range of 245.0 to 247.0 mm and a first width in the range of 70.0 to75.0 mm.
 24. The system of claim 20, wherein said second baffle has asecond length in the range of 139.0 to 141.0 mm and a second width inthe range of 96.0 to 98.0 mm.
 25. The system of claim 20, wherein eachof said impellers impart impact and shear forces to said compositionduring rotation of said apparatus.
 26. The system of claim 25, whereinthe ratio of said impact and shear forces is substantially equal to1/tan (second impeller angle).
 27. The system of claim 20, wherein saidfirst and second baffles comprise substantially flat, elongated members.28. The system of claim 27, wherein said first impeller angle extendssubstantially uniformly from said first end to said second end of saidfirst baffle.
 29. The system of claim 20, wherein said hub outerdiameter, said first and second lengths, said first and second widths,and said first, second and third impeller angles define a first blendingapparatus size have a first tip radius, said first blending apparatussize providing a first flow pattern of said composition during rotationof said apparatus.
 30. The system of claim 29, wherein said first flowpattern includes a reverse flow component.
 31. The system of claim 29,wherein said apparatus is scalable to at least a second blendingapparatus size having a second tip radius, said second blendingapparatus size providing a second flow pattern that is substantiallysimilar to said first flow pattern.